This paper is open access
https://onlinelibrary.wiley.com/doi/10.1111/cpr.13764
They were using Palmitic Acid to reduce the MMP and terazosin restored it. I am not sure that this can be carried forward to fixing a flawed mtDNA or the effects of it.
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Yes thatās the one I cited here: Terazosin / doxazosin / alfuzosin may protect against dementia with Lewy bodies - #59 by adssx
But the one I donāt have access to and that looked at MMP is this one: Terazosin / doxazosin / alfuzosin may protect against dementia with Lewy bodies - #49 by adssx
And yes youāre right, we donāt know if thatās transferable to damage from say aging.
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If it were really so simple to just increase ATP to prevent dementia, then good old creatine monohydrate might be beneficial.
I looked for information on exercise and Terrazosin, and I was surprised to find that Terrazosin is thought to have a negative effect on performance in spite of the enhanced glycolysis.
Among the remaining signals, 80 were prioritized, and five emerged as the highest priority: terazosin, tamsulosin, allopurinol, esomeprazole, and omeprazole.
Terazosin and tamsulosin, both alpha-1 adrenergic antagonists primarily used for treating benign prostatic hyperplasia and hypertension, have been associated with adverse cardiovascular effects. These drugs lower blood pressure by causing vasodilation; however, they can also lead to postural hypotension and reflex tachycardia. The cardiovascular stress induced by these side effects may increase the risk of AMI, particularly in older patients or those with pre-existing cardiovascular conditions.
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Cross-posting:
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I didnāt know there was a trial of terazosin for ALS in Oxford. āParticipants will take up to 10mg oral terazosin daily for up to 6 months.ā
āOverall study end date 31/03/2025ā
āIntention to publish date 31/03/2026ā
One year to publish the resultsā¦ Academia is a disgrace.
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Preprint + China + Mice
ADRA1 critically mediates tauopathy and neuroinflammation through STING/NF-ĪŗB/NLRP3 signaling. These results identify ADRA1 as a promising therapeutic target for AD prevention and treatment.
Consistently, pretreatment with Terazosin or AMD3100 suppressed AĪ²42-mediated elevations in p-Taus396, p-Tau202/205, p-Tau231 and total Tau5 levels, along with reduced activation of the NF-ĪŗB pathway (p-NF-ĪŗB p65/NF-ĪŗB p65) and NLRP3 inflammasome components (NLRP3, caspase-1, cleaved caspase-1, IL-1Ī², and IL-18)
Notably, Terazosin and AMD3100 also suppressed AĪ²42-induced ROS elevation in SH-SY5Y cells.
The progression of AD is marked by two synergistic pathological driversāreactive gliosis and maladaptive cytokine releaseāwhich collectively establish neuroinflammatory suppression as a non-negotiable therapeutic priority. Preclinical studies demonstrate that ADRA1 antagonist Terazosin reduces hippocampal and cortical GFAP/CD68 expression in APP/PS1 mice, whereas ADRA1 agonist phenylephrine enhances astrocytic IL-6 production. Our findings align with this paradigm, showing that neuronal ADRA1 overexpression in WT mice elevates hippocampal GFAP, Iba-1, and inflammatory cytokine levels. Notably, IL-6āa key mediator amplified in this processāactivates the STAT3/cGAS/STING signaling pathway in glial cells to propagate neuroinflammation. This suggests that IL-6 upregulation induced by neuronal ADRA1 dysregulation may initiate a self-perpetuating cycle of glial activation and neuroinflammatory exacerbation via STAT3/cGAS/STING signaling.
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After adjusting for the aforementioned potential confounding variates, CCBs (HR: 1.09, 95% CI (1.03ā1.16), p = 0.002) were independently associated with an increased risk of mechanical ventilation. In contrast, ACEI (HR: 0.90, 95% CI (0.85ā0.95), p < 0.001), alpha blockers (HR: 0.92, 95% CI (0.87ā0.97), p = 0.001), and CCB (HR: 0.93, 95% CI (0.88ā0.98), p = 0.006) were independently associated with a decreased risk for mortality (Table 2).
Interestingly, alpha blockers were associated with a protective function against death. According to the JNC-8 recommendations, alpha blockers are a 3rd-line antihypertensive treatment prescribed when hypertension is unable to be controlled by first or second-line treatments [27]. A possible mechanism for the protective effect of alpha blockers may result from their ability to reduce left ventricular hypertrophy, an independent risk factor for cardiovascular mortality and morbidity, and improve glomerular filtration rate, reducing kidney damage [35]. Given the diversity, complexity, and frequency of confounding comorbidities in hypertensive patients, prospective randomized control or propensity-matched studies are needed to study the effects of alpha blockers on COVID-19 severity.
The massive issue with alpha-1 blockers is their potential cardiotoxicityā¦
Ī±1-Adrenergic receptors prevent a maladaptive cardiac response to pressure overload 2006
These results suggest that the adverse cardiac effects of Ī±1-antagonists in clinical trials are due to loss of Ī±1-signaling in myocytes, emphasizing concern about clinical use of Ī±1-antagonists, and point to a revised perspective on sympathetic activation in heart failure.
One arm of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) in hypertension tested the Ī±1-antagonist doxazosin versus the diuretic chlorthalidone in 24,335 men and women with cardiac risk factors (5). This arm of the trial was stopped prematurely, because doxazosin doubled the incidence of heart failure, and further detailed analyses indicated a doxazosin effect to increase heart failure that was not seen with other antihypertensive medications (5ā8). Similarly, in the VasodilatorāHeart Failure Trials (V-HeFT), the Ī±1-antagonist prazosin did not improve survival as did other vasodilators and even tended to increase mortality (9). Doxazosin and prazosin are piperazinyl quinazolines, which at high doses can cause apoptosis in heart and other tissues independent of Ī±1-ARs (10, 11), and also have relatively high affinity for Ī±2-AR subtypes B and C (12, 13).
On the other hand: Unraveling the relationships between alpha- and beta-adrenergic modulation and the risk of heart failure 2023
Lower Ī±1A or Ć1 activity was associated with reduced HF risk: odds ratio (OR) 0.83 (95% CI 0.74ā0.93, P = 0.001) and 0.95 (95% CI 0.93ā0.97, P = 8 Ć 10ā6).
This study provides genetic evidence that Ī±1A or Ć1 receptor inhibition will likely decrease HF risk, while lower Ī±2B activity may increase this risk. Genetic variant analysis can assist with drug development for HF prevention.
There are contradictory data on the role of Ī±1 blockers in HF. Doxazosin and prazosin were associated with an increased risk of HF in several studies, including the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT) and another trial comparing doxazosin to chlorthalidone (3, 5, 42). However, no direct comparison between Ī±1 blockers and placebo in a large trial is available. On the contrary, non-specific Ī±1 blockers were recently associated with an improvement in death and rehospitalization for HF, and specific Ī±1A blockers with a neutral effect in a large HF cohort (6).
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Glycolysis-enhancing Ī±1-adrenergic antagonists are neuroprotective in Alzheimerās disease 2025
Preprint
Terazosin (TZ) is an Ī±1-adrenergic receptor antagonist that enhances glycolysis by activating the enzyme phosphoglycerate kinase 1 (PGK1). Epidemiological data suggest that TZ may be neuroprotective in Parkinsonās disease and in dementia with Lewy bodies and that glycolysis-enhancing drugs might be protective in other neurodegenerative diseases involving protein aggregation, such as Alzheimerās disease (AD). We investigated TZ in AD and report four main results. First, we found that TZ increased ATP levels in a Saccharomyces cerevisiae mutant with impaired energy homeostasis and reduced the aggregation of the AD-associated protein, amyloid beta (AĪ²) 42. Second, in an AD transgenic mouse model (5xFAD) we found that TZ attenuated amyloid pathology in the hippocampus and rescued cognitive impairments in spatial memory and interval timing behavioral assays. Third, using the Alzheimerās Disease Neuroimaging Initiative (ADNI) database, we found that AD patients newly started on TZ or related glycolysis-enhancing drugs had a slower progression of both cognitive dysfunction and neuroimaging biomarkers, such as 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), a measure of brain metabolism. Finally, in a large human administrative dataset, we found that patients taking TZ or related glycolysis-enhancing drugs had a lower hazard of being diagnosed with AD compared to those taking tamsulosin or 5-alpha reductase inhibitors. These data further implicate metabolism in neurodegenerative diseases and suggest that glycolysis-enhancing drugs may be neuroprotective in AD.
These charts are not super convincingā¦
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Phosphoglycerate kinase 1 as a therapeutic target in neurological disease 2025
The glycolytic enzyme phosphoglycerate kinase 1 (PGK1) has emerged as a promising therapeutic target for both Parkinsonās disease (PD) and amyotrophic lateral sclerosis (ALS). Enhancing glycolysis represents an attractive approach because neurons are particularly vulnerable to dysregulated cell metabolism.
Although clinical trials of the PGK1 agonist terazosin are underway for PD and ALS, this compound can generate significant side effects, highlighting the need to identify alternative PGK1-activating strategies and compounds.
The potential benefits of increasing PGK1 activity in other neurological conditions are less clear. Further understanding of the noncanonical roles of PGK1 is needed to determine in which conditions increased activation may be beneficial.
Although it is unlikely to be a cure, upregulating glycolysis may be beneficial across multiple neurological diseases, and alternative approaches to activate this fundamental cellular pathway beyond PGK1 need to be explored. As always when targeting such core cellular pathways, there is a need for caution because the effect on normal cell function of increasing such fundamental cell processes is so far unclear. However, current data do suggest that targeting PGK1 and glycolysis has the potential to improve or delay the course of disease for many patients affected by neurodegenerative diseases, for which the therapeutic options are currently extremely limited (see Clinicianās corner). Considering this and the growing body of supporting evidence, the benefit of increased PGK1 activity in multiple neurological conditions is worthy of further preclinical and clinical investigation.
PGK1 activity is tightly regulated at the transcriptional, post-transcriptional, and post-translational levels [7]. HIF-1 is a strong regulator of PGK1 transcription, increasing its transcription in many hypoxic conditions [7,12,13]. PGK1 can also undergo a wide range of post-transcriptional modifications, such as phosphorylation, acetylation, succinylation, O-GlcNAcylation, crotonylation, or ubiquitination [7,14,15]. These could represent additional attractive therapeutic targets that have so far been studied mainly in the context of cancer [7].
The nervous system is particularly vulnerable to low oxygen levels, with hypoxia playing a key role in multiple neurological conditions. Under systemic hypoxic conditions, hypoxia-inducible factor (HIF)-1Ī± is increased, which upregulates PGK1 as an adaptive response [59ā62]. This increased expression of PGK1 along with other glycolytic proteins has been associated with better outcomes in hypoxic-ischemic encephalopathy in infants [63]. Increasing PGK1 activity with an agonist in mouse and cell models of acute hypobaric brain injury was neuroprotective and reduced the production of ROS. It was found that PGK1 that has translocated to the mitochondria could interact with tumor necrosis factor receptor-associated protein 1, which is a mitochondrial molecular chaperone that helps to regulate production of ROS [64]. PGK1 that has translocated to the mitochondria can also phosphorylate PDHK1, inhibiting mitochondrial pyruvate metabolism and ROS while also promoting cell proliferation [65]. PGK1 is also upregulated following TBI, with higher PGK1 levels being associated with improved prognosis in patients [66]. It has been suggested that PGK1 may help to regulate the process of ferroptosis after TBI, although its precise role in this is unclear.
It is worth noting, however, that increased PGK1 activity may not always be beneficial in this context. A mouse model of postoperative cognitive dysfunction induced with etomidate found that the increased expression of HIF-1Ī± and associated increase in PGK1 resulted in increased levels of oxidative stress, with downregulation of HIF-1Ī± being protective [67]. Moreover, an in vitro oxygen-glucose deprivation/reoxygenation model of ischemic neuronal injury revealed that the translocation of PGK1 to mitochondria occurring in hypoxic conditions was associated with a decrease in cytosolic PGK1, which was found to increase neuronal cell death [16].
The multiple roles of PGK1 outside of its primary role in glycolysis are still poorly understood and may explain some of the discrepancies observed. The degree to which PGK1 activity is increased also appears to be an important factor because intraperitoneal injection of low doses of PGK1 fused with PEP-1 to cross the bloodābrain barrier reduced neuronal death in a gerbil hippocampal model of ischemia, whereas a higher dose was not found to be protective [68]. This supports previous work that showed a low dose of terazosin was protective and resulted in a lower infarct volume in a rat model of stroke, whereas a higher dose was not beneficial [69]. As discussed previously, the post-translational modifications of PGK1 may also play a significant role because hypoxia can result in a decrease in the lysine crotonylation of PGK1, and altered expression of succinylated PGK1 has been reported in a rat model of epilepsy even when total PGK1 levels were unchanged [14,15].
The evidence for targeting PGK1 activity in other neurological conditions, such as hypoxia and neuroinflammation, is mixed. Increased knowledge of the other roles of PGK1 apart from its canonical role in glycolysis will be key to understanding conditions where enhancing PGK1 activity would be appropriate.
@John_Hemming: bridging the gap between terazosin and hypoxia!
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